IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat Export

@article{citeulike:5470560, abstract = {10.1073/pnas.0810087106 Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1β. In the periphery, increased expression of IL-1β was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1β or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1β, IL-6, TNFα, KC, MCP-1, and MIP-1α) and islet CD68, MHC II, and CD53 immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1β activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1β may drive tissue inflammation that impacts on both β cell functional mass and insulin sensitivity in type 2 diabetes.}, author = {Ehses, J. A. and Lacraz, G. and Giroix, M. H. and Schmidlin, F. and Coulaud, J. and Kassis, N. and Irminger, J. C. and Kergoat, M. and Portha, B. and Homo-Delarche, F. and Donath, M. Y.}, citeulike-article-id = {5470560}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0810087106}, citeulike-linkout-1 = {http://www.pnas.org/content/106/33/13998.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/106/33/13998.full.pdf}, citeulike-linkout-3 = {http://view.ncbi.nlm.nih.gov/pubmed/19666548}, citeulike-linkout-4 = {http://www.hubmed.org/display.cgi?uids=19666548}, day = {18}, doi = {10.1073/pnas.0810087106}, journal = {Proceedings of the National Academy of Sciences}, keywords = {b-cell, il-1, inflammation, pancreas}, month = {August}, number = {33}, pages = {13998--14003}, posted-at = {2009-08-18 22:19:52}, priority = {2}, title = {IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat}, url = {http://dx.doi.org/10.1073/pnas.0810087106}, volume = {106}, year = {2009} }

TY - JOUR ID - citeulike:5470560 L3 - citeulike-article-id:5470560 N2 - 10.1073/pnas.0810087106 Recent studies suggest an inflammatory process, characterized by local cytokine/chemokine production and immune cell infiltration, regulates islet dysfunction and insulin resistance in type 2 diabetes. However, the factor initiating this inflammatory response is not known. Here, we characterized tissue inflammation in the type 2 diabetic GK rat with a focus on the pancreatic islet and investigated a role for IL-1. GK rat islets, previously characterized by increased macrophage infiltration, displayed increased expression of several inflammatory markers including IL-1β. In the periphery, increased expression of IL-1β was observed primarily in the liver. Specific blockade of IL-1 activity by the IL-1 receptor antagonist (IL-1Ra) reduced the release of inflammatory cytokines/chemokines from GK islets in vitro and from mouse islets exposed to metabolic stress. Islets from mice deficient in IL-1β or MyD88 challenged with glucose and palmitate in vitro also produced significantly less IL-6 and chemokines. In vivo, treatment of GK rats with IL-1Ra decreased hyperglycemia, reduced the proinsulin/insulin ratio, and improved insulin sensitivity. In addition, islet-derived proinflammatory cytokines/chemokines (IL-1β, IL-6, TNFα, KC, MCP-1, and MIP-1α) and islet CD68, MHC II, and CD53 immune cell infiltration were reduced by IL-1Ra treatment. Treated GK rats also exhibited fewer markers of inflammation in the liver. We conclude that elevated islet IL-1β activity in the GK rat promotes cytokine and chemokine expression, leading to the recruitment of innate immune cells. Rather than being directly cytotoxic, IL-1β may drive tissue inflammation that impacts on both β cell functional mass and insulin sensitivity in type 2 diabetes. IS - 33 JF - Proceedings of the National Academy of Sciences EP - 14003 TI - IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat VL - 106 SP - 13998 KW - b-cell KW - il-1 KW - inflammation KW - pancreas AU - Ehses, JA AU - Lacraz, G AU - Giroix, MH AU - Schmidlin, F AU - Coulaud, J AU - Kassis, N AU - Irminger, JC AU - Kergoat, M AU - Portha, B AU - Homo-Delarche, F AU - Donath, MY PY - 2009/08/18/ UR - http://dx.doi.org/10.1073/pnas.0810087106 ER -